L0301P58 - Molecular Basis of Cancer 3
Tumour Suppressor Genes (TSG) *normal cellular genes, present in all cells *includes: **cell cycle proteins **transcription factors **cell surface proteins **DNA repair proteins **apoptosis related proteins *control critical check points in the cell cycle **particularly the G1/S boundary *induce the transcription of regulatory inhibitory genes **generally genes encoded by these proteins negatively control cell growth *prevent rapid cell cycling and thereby rapid cell division and cell growth *to become cancerous, TSG become inactivated allowing cells: **to lose adhesion to neighbouring cells and spread **to no longer repair DNA causing mutations to accumulate **to escape the normal “brakes” that normally prevent rapid cell division Loss of Function of TSG *inactivating mutations can lead to cancer **main difference to oncogenes: are cancerous due to activating mutations *can be inherited (only in one copy otherwise fatal) or acquired (somatic mutations) *requires both copies of the gene to be lost for cancer to develop **i.e. “two hit hypothesis” Effects of Loss of Function *loss of one copy of a TSG —> slight cell cycle progression advantage *loss of both copies i.e. complete inactivation —> significant growth advantage which predisposes to cancer *when an individual is born with only one functioning copy, they may then lose the second copy and be predisposed to a life long cancer predisposition   Role in the Cell Cycle *function is to prevent cells from progressing through the cell cycle and allow repair of damaged DNA *when TSG is lost, cell cycle proceeds unchecked causing cells to divide at abnormal rates *requires loss of function of both copies of the gene to predispose cancer *characterised by inactivating mutations whether inherited or acquired *examples: p53 and retinoblastoma (Rb) gene product Example 1 of TSG - Retinoblastoma Gene (Rb) *widely expressed gene found in every cell in the body *acts as a regulator of cell cycle progression **prevents transcriptional activation of a variety of genes **required for the onset of S phase of the cell cycle as it: ***sequesters transcription factor E2F holding it in an inactive state ***when the cell is ready to enter S phase, Rb becomes phosphorylated and releases E2F to transcribe cyclins and CDKs *plays a role in regulating other cellular processes including differentiation, DNA replication and apoptosis *is also mutated in many other cancers: **including breast, lung, bladder tumours *in these cases the tumours arise from a complex series of genetic events in which the loss of the functional Rb genes is one of many genetic events leading to cancer Retinoblastoma *rare childhood tumour of the retina (neural precursor cells of the retina) **cells of the retina are most sensitive to lost of this gene *1/20,000 children affects *two forms of the disease: **hereditary and sporadic *both copies of the Rb gene must be lost Hereditary Retinoblastoma *develops at a very young age *tumours in both eyes *high penetrance *mutant Rb allele on chromosome 13 in every cell of the body **all body cells lack one normal copy of Rb gene leading to a growth advantage **additional acquired somatic mutation in the remaining functional copy = loss of both copies of Rb **cell with no functional copies of the gene is strongly predisposed to develop cancer *may also lead to development of cancer in other areas of the body Sporadic (Non-hereditary) Retinoblastoma *very rare **due to the fact that it requires two somatic acquired mutations in a single retinal cell to destroy both copies of the gene *one tumour in one eye *develops at a later age *chromosomal changes only in tumour cells Example 2 of TSG - Protein 53 (P53) *induces specific cell responses, including: **cell cycle arrest (G0), senescence (ageing), cell differentiation, apoptosis *contributes to DNA repair following damage *if cell DNA damage is severe, p53 will induce cell death **preventing replication of damaged or mutated DNA **depends on the ability of p53 to induce gene expression, with selective activation of p53 target genes *normal p53 activation inhibits cell growth (through cell-cycle arrest or induction of apoptosis) = prevents tumour development **occurs when signals induce p53 by stabilising the p53 protein, which leads to an increase in cellular p53 levels Squamous Cell Cancer (SCC) *most SCC’s induced by sun exposure *at least one copy of p53 lost early in sun damaged skin *p53 gene is mutated in up to 90% of SCC’s **hallmark UV light induced C-T substitution *loss of one copy confers growth advantage (probably due to decreased apoptosis) *p53 mutations relevant but not sufficient to cause skin cancer on its own **i.e. accumulation of mutations including Ras oncogene P53 in Cancer *cancer cells survive because they have developed the molecular mechanisms to evade cell death (apoptosis) *one of the most common mutations = p53 **50% of all tumours show mutations and loss of function of p53 *cancer cell acquisition of p53 mutations: **often occurs early in cancer development **commonly, the mutation are a single point mutation **allows the tumour to escape apoptosis **DNA damage is not repaired ***no halt to the cell cycle at the check points to repair damaged DNA **cells may survive and proliferate with a mutated genome ***often chromosomes become fragmented, and incorrectly rejoined creating an increasingly mutated genome (after successive rounds of cell division) Mismatch Repair Genes (MMR) *repair DNA if errors occur in DNA replication *humans have 8 MMR genes **classified into: MSH, MLH, PMS *often lost or defective in cancers *follow “two-hit” hypothesis leading to cells which are deficient in mismatch repair **i.e. cell lines with mutation in only one copy of MSH2 are able to perform mismatch repair where as those with both copies of mutated were deficient in mismatch repair, leading to cancer Mutations in MMR *both sporadic and hereditary colorectal cancers have defects in these genes *tumour DNA: many alterations in short-repeated sequences (microsatellite repeats) *findings suggest that replication errors by DNA polymerase had occurred during tumour development and not been repaired *this phenotype is termed replication error positive (RER) or microsatellite instability *RER’s seen in colorectal, endometrial, breast, prostate, lung and stomach cancers Summary *cancer occurs when multiple genes are affected: **activation of oncogenes **loss of tumour suppressor genes **loss of mismatch repair genes